'An Inconvenient Truth': Add Bev or Chemo to TKIs in Lung Cancer

Hello. This is Mark Kris from Memorial Sloan Kettering, speaking about developments in the treatment of EGFR-mutant lung cancers.

This year, at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), we had a fantastic presentation on the discovery and development of epidermal growth factor receptor (EGFR) inhibitors in patients with EGFR-mutant lung cancers in the opening address by Dr Bruce Johnson, a member of one of the teams that discovered the EGFR mutation and its consequence of imparting sensitivity to tyrosine kinase inhibitors (TKIs) in cancer cells bearing that mutation.

I think there is growing consensus that osimertinib is the TKI of choice. It is a better TKI. It has fewer side effects and wild-type effects, particularly diarrhea and rash. There was another important issue in the poster I presented, which was that a substantial proportion of patients with EGFR-mutant lung cancers develop brain metastases while under treatment.

You can see from the randomized trials where osimertinib was compared with gefitinib or erlotinib that it had a better ability to prevent the development of brain metastases, which also are horribly disruptive and impart a shorter life. Another reason to give osimertinib up front, as if we didn't have enough reasons already, is that it can help cut down on the development of brain metastases. All TKIs treat brain metastases equally effectively, but the development is something unique to osimertinib.

The next question is, what is the next step? Yes, we occasionally find people with MET or HER2 abnormalities that develop in the acquired resistance setting. They are very rare and, of course, when you find them, they should be treated, but they are not what we are going to find in the majority of patients. Therefore, we need agents that we can couple with our best TKIs to improve progression-free survival.

Two things came up at the ASCO meeting this year. Two papers presented updates of a phase 2 trial and a phase 3 trial, showing a clear improvement in progression-free survival when you add bevacizumab to erlotinib. Clearly, bevacizumab, an available drug, can be added to erlotinib. It is a standard of care in Europe and has been approved by European regulatory agencies, which gives us a medication we can add today.

The second medication that could be added is standard chemotherapy. I think many people at the ASCO meeting listened to a very inconvenient truth. In a clinical trial, patients who received chemotherapy plus gefitinib with EGFR-mutant lung cancers did better than people who only had gefitinib. That information has been out there all along. People know that chemotherapy is effective. In the IPASS trial, you could see that chemotherapy is even more effective in patients with EGFR mutation.[1] It likely could attack persisting cells that were not killed by the EGFR TKI. There are both practical and theoretical reasons to give chemotherapy.

We have two strategies available today to add to EGFR TKIs to improve progression-free survival for our patients. One is to add bevacizumab and the other is to add chemotherapy. I know they are fairly unpopular. There has been little uptake—at least here in the United States—of adding bevacizumab, but I think the data are extremely clear that [adding bevacizumab] can improve progression-free survival. Progression is a devastating development for our patients, both emotionally and physically. We are trying to [extend] PFS, and there are excellent data now from two trials to say we can do that.

I urge you to think beyond just giving osimertinib. I know this is a bit of an extrapolation, but we have very good data demonstrating that adding bevacizumab or chemotherapy can improve progression-free survival beyond what we can achieve with a TKI. We have to give the best TKI. We have the opportunity to improve upon the benefits of osimertinib by adding either chemotherapy or bevacizumab. It is hard to say which one is best today. Obviously, there are no direct comparisons. In general, there is more widespread use and acceptance of bevacizumab with the TKI, but there is not consensus on that.

I urge you to use every tool available to improve progression-free survival in our patients with EGFR-mutant lung cancers. This ASCO meeting gave us good support for two tools—bevacizumab and chemotherapy.

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